Exagamglogene Autotemcel Shows Promise in Treatment of Transfusion-Dependent β-Thalassemia

For patients with transfusion-dependent β-thalassemia (TDT), significant transfusion independence outcomes were achieved with myeloablation followed by exagamglogene autotemcel (exa-cel) treatment, according to a study published in The New England Journal of Medicine.¹

Patient Receiving Blood Transfusion | Elnur - stock.adobe.com

TDT is the most severe type of β-thalassemia.² Affected patients are often diagnosed at a young age with a mutation in the β-globin (HBB) gene, which contributes to sparsity in healthy, oxygen-carrying red blood cells. Without the ability to transport enough oxygen throughout the body, individuals endure chronic, potentially life-threatening anemia. As a result, the management of this condition requires regular blood transfusions that can take place as frequently as every 3-4 weeks.

At present, allogeneic hematopoietic stem-cell transplantation is a potentially curative treatment route for this patient population; however, a myriad of risks are associated with this option, including graft rejection, complications, or even death related to the transplantation.¹ In response, alternative interventions such as exa-cel, a non-viral cell therapy, have been in development to target the underlying pathophysiology of TDT. Exa-cel, the present authors explained, is designed to reactivate fetal hemoglobin synthesis, which has previously demonstrated capability to lessen morbidity and mortality rates in patients with TDT. The authors continued by noting how patients with TDT are transfusion-free when their levels of fetal hemoglobin are higher.

To investigate the efficacy of exa-cel treatment in eliminating the need for transfusions, researchers have been conducting an ongoing, phase 3 trial on the impact of single-dose exa-cel. Patients between the ages of 12-35 years were recruited across 13 sites throughout the US, UK, Germany, Canada, and Italy. Exa-cel was administered intravenously through a central venous catheter and began 2-7 days following a busulfan infusion.

The study period lasted 2 years, with a follow-up 16 months after infusion. Afterward, patients were offered the chance to enroll in a 13-year follow-up study. The primary end point was achieved if an individual reached transfusion independence (9 g/dL average hemoglobin level that was maintained for at least 12 months without the need for red-cell transfusion).

In this prespecified interim analysis, 52 patients with TDT had received exa-cel, with a median follow-up of 20.4 months. To date, sufficient follow-up data have been gathered from 35 patients, 32 of whom achieved transfusion independence (91%; 95% CI, 77-98; P < .001). Among this group of participants, hemoglobin and fetal hemoglobin levels were reportedly 13.1 g/dL and 11.9 g/dL throughout their transfusion independence, respectfully. Transfusions stopped for these patients, on average, approximately 35 days after their exa-cel infusion. Additionally, at the 6-month mark, 94% of these patients’ red cells expressed fetal hemoglobin.

In the overall study population, 48 of the 52 patients (92%) were transfusion-free for 0.3-45.1 months, beginning at the 60-day mark since their last red-cell transfusion.

The majority of adverse events (AEs) occurred in the first 6 months, and all patients reported experiencing at least 1 AE. A total of 46 (88%) patients experienced an event classified as grade 3 or 4 in severity, which includes incidents such as anemia, stomatitis, mucosal inflammation, nausea, among others. A serious adverse event—namely veno-occlusive liver disease—occurred in 17 patients (33%) and was attributed to busulfan regimens.

The authors concluded, “the durability of the benefit of exa-cel treatment is supported by the stable percentages of BCL11A alleles maintained in both nucleated peripheral blood cells and bone marrow CD34+ cells. Allelic editing in peripheral blood was detected within 1 month after the exa-cel infusion, and the mean percentage of alleles with the intended genetic modification generally remained stable after month 2.” Results from this process further bolstered the perceived efficacy of one-time exa-cel infusion in the treatment and management of TDT, as well as improve the quality of life for affected patients.

References

1. Locatelli F, Lang P, Wall D, et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. N Engl J Med. 2024. doi:10.1056/NEJMoa2309673

2. Beta-thalassemia (beta-thal). Bluebird Bio. Updated July 2023. Accessed April 26, 2024. https://www.bluebirdbio.com/our-focus/beta-thalassemia